EP4169914A1

EP4169914A1 - Salt of compound and pharmaceutical composition containing salt

Info

Publication number: EP4169914A1
Application number: EP21828291.1A
Authority: EP
Inventors: Chenggang ZHU; Xuan YANG; Chaochun Zhang; Liangliang XU
Original assignee: Shenzhen Forward Pharmaceuticals Co Ltd
Current assignee: Shenzhen Forward Pharmaceuticals Co Ltd
Priority date: 2020-06-23
Filing date: 2021-06-23
Publication date: 2023-04-26
Also published as: KR20230026384A; AU2021294553A1; JP2023531078A; WO2021259316A1; CN116075504A; CN115734968A; KR20230026383A; US20230234941A1; WO2021259315A1; EP4169915A1; AU2021294796A1; JP2023531077A

Abstract

The present application relates to a salt formed from a compound of formula (I) with an acid: wherein the acid is selected from hydrochloric acid, methanesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, maleic acid, hydrobromic acid, citric acid, L-tartaric acid, and p-toluenesulfonic acid. The present application also relates to a method for treating non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutation using the salt.

Description

Technical Field

Background Art

Chinese patent CN105461695B discloses a compound of formula (I), which have multiple basic centers. The inhibitory activity of the compound against EGFR activating mutation (such as exon 19 deletion activating mutation, L858R activating mutation, T790M drug resistance mutation and exon 20 insertion mutation) is significantly higher than the inhibitory activity against wild-type EGFR (WT EGFR), and therefore, the compound has higher selectivity and safety, and lower toxic and side effects.
Salt formation studies are usually carried out on organic basic compounds having activity. However, those skilled in the art cannot predict with which acids a specific organic basic compound can form stable salts, or whether a specific organic basic compound or its acid addition salt is more suitable for further drug development, let alone which salt formed has better chemical stability, physical stability or solubility, and which salt has all these better properties. In particular, if an organic basic compound has multiple basic centers, it is impossible for those skilled in the art to predict whether its salts formed with a specific acid in various equivalent ratios have the same properties or different properties, let alone which equivalent ratio of the organic basic compound to the acid is more suitable for further drug development.

Summary of the Invention

The present application seeks to find salts of the compound of formula (I) suitable for further drug development. In particular, the present application seeks to find salts with properties suitable for further drug development, including a reasonable salt-forming equivalent ratio, better chemical stability, better physical stability and/or better solubility.
In one aspect according to the invention, the present application relates to a salt formed from the compound of formula (I) with an acid:
wherein the acid is selected from hydrochloric acid, methanesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, maleic acid, hydrobromic acid, citric acid, L-tartaric acid, and p-toluenesulfonic acid.
In another aspect according to the invention, the present application relates to a pharmaceutical composition comprising the salt according to the invention, which comprises the salt according to the invention and a pharmaceutically acceptable carrier.
In still another aspect according to the invention, the present application relates to a method of treating non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutation, comprising administering the salt according to the invention to a patient.
In a further aspect according to the invention, the present application relates to the use of the salt according to the invention in the preparation of a medicament for the treatment of non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutation.

Brief Description of the Drawings

Figure 1: XRPD pattern of the amorphous free base (Sample No. Y11526-45-RV-FWD1509-AF-SU12).
Figure 2: DSC profile of the amorphous free base (Sample No. Y11526-45-RV-FWD1509-AF-SU12).
Figure 3: TGA profile of the amorphous free base (Sample No. Y11526-45-RV-FWD1509-AF-SU12).
Figure 4: ¹ H-NMR spectrum of the amorphous free base (Sample No. Y11526-45-RV FWD1509-AF-SU12).
Figure 5: PLM photograph of the amorphous free base (Sample No. Y11526-45-RV-FWD1509-AF-SU12).
Figure 6: XRPD pattern of the amorphous 1 eq. (equivalent) hydrochloride salt (Sample No. Y11526-42-SU11-methanol-dichloromethane).
Figure 7: DSC profile of the amorphous 1 eq. hydrochloride salt (Sample No. Y11526-42-SU11-methanol-dichloromethane).
Figure 8: TGA profile of the amorphous 1 eq. hydrochloride salt (Sample No. Y11526-42-SU11-methanol-dichloromethane).
Figure 9: ¹ H-NMR spectrum of the amorphous 1 eq. hydrochloride salt (Sample No. Y11526-42-SU11-methanol-dichloromethane).
Figure 10: PLM photograph of the amorphous 1 eq. hydrochloride salt (Sample No. Y11526-42-SU11-methanol-dichloromethane).
Figure 11: XRPD pattern of the amorphous 2 eq. hydrochloride salt (Sample No. Y11526-28-SUS-methanol-dichloromethane).
Figure 12: DSC profile of the amorphous 2 eq. hydrochloride salt (Sample No. Y11526-28-SUS-methanol-dichloromethane).
Figure 13: TGA profile of the amorphous 2 eq. hydrochloride salt (Sample No. Y11526-28-SUS-methanol-dichloromethane).
Figure 14: ¹ H-NMR spectrum of the amorphous 2 eq. hydrochloride salt (Sample No. Y11526-28-SUS-methanol-dichloromethane).
Figure 15: PLM photograph of the amorphous 2 eq. hydrochloride salt (Sample No. Y11526-28-SUS-methanol-dichloromethane).
Figure 16: XRPD pattern of the amorphous 1 eq. mesylate salt (Sample No. Y11526-42-SU10-methanol-dichloromethane).
Figure 17: DSC profile of the amorphous 1 eq. mesylate salt (Sample No. Y11526-42-SU10-methanol-dichloromethane).
Figure 18: TGA profile of the amorphous 1 eq. mesylate salt (Sample No. Y11526-42-SU10-methanol-dichloromethane).
Figure 19: ¹ H-NMR spectrum of the amorphous 1 eq. mesylate salt (Sample No. Y11526-42-SU10-methanol-dichloromethane).
Figure 20: PLM photograph of the amorphous 1 eq. mesylate salt (Sample No. Y11526-42-SU10-methanol-dichloromethane).
Figure 21: XRPD pattern of the amorphous 2 eq. mesylate salt (Sample No. Y11526-28-SU4-methanol-dichloromethane).
Figure 22: DSC profile of the amorphous 2 eq. mesylate salt (Sample No. Y11526-28-SU4-methanol-dichloromethane).
Figure 23: TGA profile of the amorphous 2 eq. mesylate salt (Sample No. Y11526-28-SU4-methanol-dichloromethane).
Figure 24: ¹ H-NMR spectrum of the amorphous 2 eq. mesylate salt (Sample No. Y11526-28-SU4-methanol-dichloromethane).
Figure 25: PLM photograph of the amorphous 2 eq. mesylate salt (Sample No. Y11526-28-SU4-methanol-dichloromethane).
Figure 26: XRPD pattern of the amorphous 1 eq. besylate salt (Sample No. Y11526-42-SU9-methanol-dichloromethane).
Figure 27: DSC profile of the amorphous 1 eq. besylate salt (Sample No. Y11526-42-SU9-methanol-dichloromethane).
Figure 28: TGA profile of the amorphous 1 eq. besylate salt (Sample No. Y11526-42-SU9-methanol-dichloromethane).
Figure 29: ¹ H-NMR spectrum of the amorphous 1 eq. besylate salt (Sample No. Y11526-42-SU9-methanol-dichloromethane).
Figure 30: PLM photograph of the amorphous 1 eq. besylate salt (Sample No. Y11526-42-SU9-methanol-dichloromethane).
Figure 31: XRPD pattern of the amorphous 2 eq. besylate salt (Sample No. Y11526-30-SU1-water).
Figure 32: DSC profile of the amorphous 2 eq. besylate salt (Sample No. Y11526-30-SU1-water).
Figure 33: TGA profile of the amorphous 2 eq. besylate salt (Sample No. Y11526-30-SU1-water).
Figure 34: ¹ H-NMR spectrum of the amorphous 2 eq. besylate salt (Sample No. Y11526-30-SU1-water).
Figure 35: PLM photograph of the amorphous 2 eq. besylate salt (Sample No. Y11526-30-SU1-water).
Figure 36: XRPD pattern of the amorphous 1 eq. esylate salt (Sample No. Y11526-28-SU7-methanol-dichloromethane).
Figure 37: DSC profile of the amorphous 1 eq. esylate salt (Sample No. Y11526-28-SU7-methanol-dichloromethane).
Figure 38: TGA profile of the amorphous 1 eq. esylate salt (Sample No. Y11526-28-SU7-methanol-dichloromethane).
Figure 39: ¹ H-NMR spectrum of the amorphous 1 eq. esylate salt (Sample No. Y11526-28-SU7-methanol-dichloromethane).
Figure 40: PLM photograph of the amorphous 1 eq. esylate salt (Sample No. Y11526-28-SU7-methanol-dichloromethane).
Figure 41: XRPD pattern of the amorphous 1 eq. maleate salt (Sample No. Y11526-30-SU2-water).
Figure 42: DSC profile of the amorphous 1 eq. maleate salt (Sample No. Y11526-30-SU2-water).
Figure 43: TGA profile of the amorphous 1 eq. maleate salt (Sample No. Y11526-30-SU2-water).
Figure 44: ¹ H-NMR spectrum of the amorphous 1 eq. maleate salt (Sample No. Y11526-30-SU2-water).
Figure 45: PLM photograph of the amorphous 1 eq. maleate salt (Sample No. Y11526-30-SU2-water).
Figure 46: XRPD pattern of the crystalline 1 eq. hydrobromide salt (Sample No. Y11526-33-SU8-methanol-dichloromethane).
Figure 47: DSC profile of the crystalline 1 eq. hydrobromide salt (Sample No. Y11526-33-SU8-methanol-dichloromethane).
Figure 48: TGA profile of the crystalline 1 eq. hydrobromide salt (Sample No. Y11526-33-SU8-methanol-dichloromethane).
Figure 49: ¹ H-NMR spectrum of the crystalline 1 eq. hydrobromide salt (Sample No. Y11526-33-SU8-methanol-dichloromethane).
Figure 50: PLM photograph of the crystalline 1 eq. hydrobromide salt (Sample No. Y11526-33-SU8-methanol-dichloromethane).
Figure 51: XRPD pattern of the amorphous nitrate salt (Sample No. Y11526-18-RV7-methanol-dichloromethane).
Figure 52: ¹ H-NMR spectrum of the amorphous nitrate salt (Sample No. Y11526-18-RV7-methanol-dichloromethane).
Figure 53: XRPD pattern of the amorphous sulfate salt (Sample No. Y11526-15-RV3-methanol-dichloromethane).
Figure 54: DSC profile of the amorphous sulfate salt (Sample No. Y11526-15-RV3-methanol-acetonitrile).
Figure 55: TGA profile of the amorphous sulfate salt (Sample No. Y11526-15-RV3-methanol-acetonitrile).
Figure 56: ¹ H-NMR spectrum of the amorphous sulfate salt (Sample No. Y11526-15-RV3-methanol-acetonitrile).
Figure 57: PLM photograph of the amorphous sulfate salt (Sample No. Y11526-15-RV3-methanol-acetonitrile).
Figure 58: XRPD pattern of the amorphous 2 eq. p-tosylate salt (Sample No. Y11526-23-FD11-water).
Figure 59: DSC profile of the amorphous 2 eq. p-tosylate salt (Sample No. Y11526-23-FD11-water).
Figure 60: TGA profile of the amorphous 2 eq. p-tosylate salt (Sample No. Y11526-23-FD11-water).
Figure 61: ¹ H-NMR spectrum of the amorphous 2 eq. p-tosylate salt (Sample No. Y11526-23-FD11-water).
Figure 62: PLM photograph of the amorphous 2 eq. p-tosylate salt (Sample No. Y11526-23-FD11-water).
Figure 63: photograph of the amorphous 2 eq. p-tosylate salt (Sample No. Y11526-23-FD11-water).
Figure 64: XRPD pattern of the amorphous sulfosalicylate salt (Sample No. Y11526-25-FD 13-1,4-dioxane).
Figure 65: DSC profile of the amorphous sulfosalicylate salt (Sample No. Y11526-25-FD 13-1,4-dioxane).
Figure 66: TGA profile of the amorphous sulfosalicylate salt (Sample No. Y11526-25-FD 13-1,4-dioxane).
Figure 67: ¹ H-\NMR spectrum of the amorphous sulfosalicylate salt (Sample No. Y11526-25-FD13-1,4-dioxane).
Figure 68: PLM photograph of the amorphous sulfosalicylate salt (Sample No. Y11526-25-FD 13-1,4-dioxane).
Figure 69: XRPD pattern of the amorphous sulfosalicylate salt (Sample No. Y11526-25-FD12-1,4-dioxane).
Figure 70: DSC profile of the amorphous sulfosalicylate salt (Sample No. Y11526-25-FD12-1,4-dioxane).
Figure 71: TGA profile of the amorphous sulfosalicylate salt (Sample No. Y11526-25-FD12-1,4-dioxane).
Figure 72: ¹ H-NMR spectrum of the amorphous sulfosalicylate salt (Sample No. Y11526-25-FD12-1,4-dioxane).
Figure 73: PLM photograph of the amorphous sulfosalicylate salt (Sample No. Y11526-25-FD12-1,4-dioxane).
Figure 74: XRPD pattern of the amorphous L-malate salt (Sample No. Y11526-17-RV6-methanol-dichloromethane).
Figure 75: DSC profile of the amorphous L-malate salt (Sample No. Y11526-17-RV6-methanol-dichloromethane).
Figure 76: TGA profile of the amorphous L-malate salt (Sample No. Y11526-17-RV6-methanol-dichloromethane).
Figure 77: ¹ H-NMR spectrum of the amorphous L-malate salt (Sample No. Y11526-17-RV6-methanol-dichloromethane).
Figure 78: PLM photograph of the amorphous L-malate salt (Sample No. Y11526-17-RV6-methanol-dichloromethane).
Figure 79: XRPD pattern of the amorphous 1 eq. citrate salt (Sample No. Y11526-10-FD6-1,4-dioxane).
Figure 80: DSC profile of the amorphous 1 eq. citrate salt (Sample No. Y11526-10-FD6-1,4-dioxane).
Figure 81: TGA profile of the amorphous 1 eq. citrate salt (Sample No. Y11526-10-FD6-1,4-dioxane).
Figure 82: ¹ H-NMR spectrum of the amorphous 1 eq. citrate salt (Sample No. Y11526-10-FD6-1,4-dioxane).
Figure 83: PLM photograph of the amorphous 1 eq. citrate salt (Sample No. Y11526-10-FD6-1,4-dioxane).
Figure 84: XRPD pattern of the amorphous 1 eq. L-tartrate salt (Sample No. Y11526-10-FD7-1,4-dioxane).
Figure 85: DSC profile of the amorphous 1 eq. L-tartrate salt (Sample No. Y11526-10-FD7-1,4-dioxane).
Figure 86: TGA profile of the amorphous 1 eq. L-tartrate salt (Sample No. Y11526-10-FD7-1,4-dioxane).
Figure 87: ¹ H-NMR spectrum of the amorphous 1 eq. L-tartrate salt (Sample No. Y11526-10-FD7-1,4-dioxane).
Figure 88: HPLC chromatogram overlay of the amorphous 1 eq. L-tartrate salt (Sample No. Y11526-10-FD7-1,4-dioxane).
Figure 89: XRPD overlay of the amorphous free base in a solid storage stability test, in which from top to bottom, the first trace is the XRPD of the crystalline free base as a control, the second trace is the solid obtained in Test BS2, the third trace is the XRPD of the solid obtained in Test BS1, and the fourth trace is the XRPD of the original solid.
Figure 90: XRPD overlay of the amorphous 1 eq. hydrochloride salt in a solid storage stability test, in which the upper trace is the XRPD of the solid obtained in Test BS2, the middle trace is the XRPD of the solid obtained in Test BS1, and the lower trace is the XRPD of the original solid.
Figure 91: XRPD overlay of the amorphous 2 eq. hydrochloride salt in a solid storage stability test, in which the upper trace is the XRPD of the solid obtained in Test BS2, the middle trace is the XRPD of the solid obtained in Test BS1, and the lower trace is the XRPD of the original solid.
Figure 92: Photograph of the amorphous 2 eq. hydrochloride salt in a solid storage stability test, in which the left picture is the photograph of the original solid, and the right picture is the photograph of the solid obtained in Test BS1.
Figure 93: XRPD overlay of the amorphous 1 eq. mesylate salt in a solid storage stability test, in which the upper trace is the XRPD of the solid obtained in Test BS2, the middle trace is the XRPD of the solid obtained in Test BS1, and the lower trace is the XRPD of the original solid.
Figure 94: XRPD overlay of the amorphous 2 eq. mesylate salt in a solid storage stability test, in which the upper trace is the XRPD of the solid obtained in Test BS2, the middle trace is the XRPD of the solid obtained in Test BS1, and the lower trace is the XRPD of the original solid.
Figure 95: Photograph of the amorphous 2 eq. mesylate salt in a solid storage stability test, in which the left picture is the photograph of the original solid, the middle picture is the photograph of the solid obtained in Test BS1, and the right picture is the photograph of the solid obtained in Test BS2.
Figure 96: XRPD overlay of the amorphous 1 eq. besylate salt in a solid storage stability test, in which the upper trace is the XRPD of the solid obtained in Test BS2, the middle trace is the XRPD of the solid obtained in Test BS1, and the lower trace is the XRPD of the original solid.
Figure 97: Photograph of the amorphous 2 eq. besylate salt in a solid storage stability test, in which the left picture is the photograph of the original solid, and the right picture is the photograph of the solid obtained in Test BS1.
Figure 98: XRPD overlay of the amorphous 2 eq. besylate salt in a solid storage stability test, in which the upper trace is the XRPD of the solid obtained in Test BS2, and the lower trace is the XRPD of the original solid.
Figure 99: Photograph of the amorphous 1 eq. esylate salt in a solid storage stability test, in which the left picture is the photograph of the original solid, and the right picture is the photograph of the solid obtained in Test BS1.
Figure 100: XRPD overlay of the amorphous 1 eq. esylate salt in a solid storage stability test, in which the upper trace is the XRPD of the solid obtained in Test BS2, and the lower trace is the XRPD of the original solid.
Figure 101: XRPD overlay of the amorphous 1 eq. maleate salt in a solid storage stability test, in which the upper trace is the XRPD of the solid obtained in Test BS2, the middle trace is the XRPD of the solid obtained in Test BS1, and the lower trace is the XRPD of the original solid.
Figure 102: Photograph of the amorphous 1 eq. maleate salt in a solid storage stability test, in which the left picture is the photograph of the original solid, and the right picture is the photograph of the solid obtained in Test BS1.
Figure 103: XRPD overlay of the crystalline 1 eq. hydrobromide salt in a solid storage stability test, in which the upper trace is the XRPD of the solid obtained in Test BS2, the middle trace is the XRPD of the solid obtained in Test BS1, and the lower trace is the XRPD of the original solid.
Figure 104: XRPD pattern of the solid of the crystalline 1 eq. hydrobromide salt obtained in a 2 h solid solubility test, in which the upper trace is the XRPD of the solid obtained in the 2 h solid solubility test, and the lower trace is the XRPD of the original solid.

Detailed Description of the Invention

In one aspect, the present application relates to a salt formed from a compound of formula (I) with an acid:
wherein the acid is selected from hydrochloric acid, methanesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, maleic acid, hydrobromic acid, citric acid, L-tartaric acid, and p-toluenesulfonic acid. Preferably, the acid is selected from hydrochloric acid, methanesulfonic acid, and maleic acid. More preferably, the equivalent ratio of the compound of formula (I) to the acid is 1: 1 or 1:2. Further preferably, the acid is methanesulfonic acid. More further preferably, the equivalent ratio of the compound of formula (I) to the acid is 1: 1.
The inventors of the present application have found that when the compound of formula (I) is reacted with an organic or inorganic acid, it is unexpected that the compound of formula (I) can form salts with some acids, but cannot form salts with other acids at all.
More surprisingly, when the compound of formula (I) is reacted with an acid selected from hydrochloric acid, methanesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, maleic acid, hydrobromic acid, sulfosalicylic acid, L-malic acid, citric acid, or L-tartaric acid in a molar charge ratio of compound of formula (I):acid of 1:1, some of the salts formed have a stoichiometric ratio of compound of formula (I):acid of 1:1, while the compound of formula (I) and some acids cannot form salts having a stoichiometric ratio of compound of formula (I):acid of 1:1. Specifically:
hydrochloric acid, methanesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, maleic acid, hydrobromic acid, citric acid, and L-tartaric acid enable the resulting salts to have a stoichiometric ratio of compound of formula (I):acid of 1:1 (the corresponding salts are hereinafter referred to as 1 eq. hydrochloride salt, 1 eq. mesylate salt, 1 eq. besylate salt, 1 eq. esylate salt, 1 eq. maleate salt, 1 eq. hydrobromide salt, 1 eq. citrate salt and 1 eq. L-tartrate, respectively), while sulfosalicylic acid and L-malic acid cannot enable the resulting salts to have a stoichiometric ratio of compound of formula (I): acid of 1:1.
In addition, more surprisingly, when the compound of formula (I) is reacted with an acid selected from hydrochloric acid, methanesulfonic acid, benzenesulfonic acid, nitric acid, sulfuric acid, p-toluenesulfonic acid, or sulfosalicylic acid in a molar charge ratio of compound of formula (I):acid of 1:2, some of the salts formed have a stoichiometric ratio of compound of formula (I):acid of 1:2, while the compound of formula (I) and some acids cannot form salts having a stoichiometric ratio of compound of formula (I):acid of 1:2. Specifically:
hydrochloric acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid enable the resulting salts to have a stoichiometric ratio of compound of formula (I):acid of 1:2 (the corresponding salts are hereinafter referred to as 2 eq. hydrochloride salt, 2 eq. mesylate salt, 2 eq. besylate salt, and 2 eq. p-tosylate salt, respectively), while nitric acid, sulfuric acid, and sulfosalicylic acid cannot enable the resulting salts to have a stoichiometric ratio of compound of formula (I):acid of 1:2.
More specifically, the salts obtained as above include 1 eq. hydrochloride salt, 1 eq. mesylate salt, 1 eq. besylate salt, 1 eq. esylate salt, 1 eq. maleate salt, 1 eq. hydrobromide salt, 1 eq. citrate salt, 1 eq. L-tartrate, 2 eq. hydrochloride salt, 2 eq. mesylate salt, 2 eq. besylate salt and 2 eq. p-tosylate salt, and sulfosalicylate salt, L-malate salt, nitrate salt, and sulfate salt that do not have a reasonable salt-forming equivalent ratio. For example, the salts obtained as above include amorphous 1 eq. hydrochloride salt, amorphous 1 eq. mesylate salt, amorphous 1 eq. besylate salt, amorphous 1 eq. esylate salt, amorphous 1 eq. maleate salt, crystalline 1 eq. hydrobromide salt, amorphous 1 eq. citrate salt, amorphous 1 eq. L-tartrate, amorphous 2 eq. hydrochloride salt, amorphous 2 eq. mesylate salt, amorphous 2 eq. besylate salt and amorphous 2 eq. p-tosylate salt, and amorphous sulfosalicylate salt, amorphous L-malate salt, amorphous nitrate salt, and amorphous sulfate salt that do not have a reasonable salt-forming equivalent ratio.
It is crucial for drug development whether the salts obtained as above have chemical and physical stability at the end of the preparation. The chemical and physical stability of the salts at the end of the preparation includes:

the chemical stability of the salts at the end of the preparation, that is, the purity of the salts obtained at the end of the preparation is not significantly reduced compared with the purity of the free base used to prepare the salts; and
the physical stability of the salts at the end of the preparation, that is, the salts do not undergo crystal phase transformation, moisture absorption and/or color change, etc. immediately at the end of the preparation.

Different salts behave differently in terms of chemical and physical stability at the end of the preparation, indicating that it is unpredictable how a certain salt behaves. Specifically:

1 eq. citrate salt, 1 eq. L-tartrate, nitrate salt and L-malate salt are chemically unstable at the end of the preparation;
2 eq. p-tosylate salt and sulfate salt are physically unstable at the end of the preparation; and
1 eq. hydrochloride salt, 2 eq. hydrochloride salt, 1 eq. mesylate salt, 2 eq. mesylate salt, 1 eq. besylate salt, 2 eq. besylate salt, 1 eq. esylate salt, 1 eq. maleate salt, 1 eq. hydrobromide salt, and sulfosalicylate salt are chemically and physically stable at the end of the preparation.

The salts as above which have a reasonable salt-forming equivalent ratio and are chemically and physically stable at the end of the preparation include 1 eq. hydrochloride salt, 2 eq. hydrochloride salt, 1 eq. mesylate salt, 2 eq. mesylate salt, 1 eq. besylate salt, 2 eq. besylate salt, 1 eq. esylate salt, 1 eq. maleate salt, and 1 eq. hydrobromide salt. It is also crucial for drug development whether these salts remain chemically and physically stable after storage. The chemical and physical stability of the salts after storage includes:

the chemical stability of the salts after storage, that is, the purity of the salts after storage is not significantly reduced compared with the purity of the salts before storage; and
the physical stability of the salts after storage, that is, the salts do not undergo crystal phase transformation, moisture absorption and/or color change, etc. after storage.

Different salts behave differently in terms of chemical and physical stability after storage, indicating that it is unpredictable how a certain salt behaves. Specifically:

1 eq. hydrochloride salt, 1 eq. besylate salt, and 1 eq. maleate salt are chemically unstable under storage conditions of "solid/25°C/60%RH/open/1 week" and/or "solid/60°C/closed container/1 week";
2 eq. hydrochloride salt, 2 eq. mesylate salt, 2 eq. besylate salt, 1 eq. esylate salt, and 1 eq. maleate salt are physically unstable under storage conditions of "solid/25°C/60%RH/open/1 week" and/or "solid/60°C/closed container/1 week"; and
1 eq. mesylate salt and 1 eq. hydrobromide salt are chemically and physically stable under storage conditions of "solid/25°C/60%RH/open/1 week" and "solid/60°C/closed container/1 week".

The salts as above which have a reasonable salt-forming equivalent ratio and are chemically and physically stable at the end of the preparation include 1 eq. hydrochloride salt, 2 eq. hydrochloride salt, 1 eq. mesylate salt, 2 eq. mesylate salt, 1 eq. besylate salt, 2 eq. besylate salt, 1 eq. esylate salt, 1 eq. maleate salt, and 1 eq. hydrobromide salt. It is also crucial for drug development whether these salts have better solubility. Different salts have different solubility, indicating that it is unpredictable what solubility a certain salt may have. Specifically:

2 eq. besylate salt and 1 eq. hydrobromide salt do not achieve a solubility of 2 mg/mL in some solvents that mimic physiological conditions; and
1 eq. hydrochloride salt, 2 eq. hydrochloride salt, 1 eq. mesylate salt, 2 eq. mesylate salt, 1 eq. besylate salt, 1 eq. esylate salt, and 1 eq. maleate salt have a solubility greater than 2 mg/mL in various solvents that mimic physiological conditions.

As can be seen from the above contents, 1 eq. mesylate salt surprisingly and unexpectedly has a reasonable salt-forming equivalent ratio, better chemical stability, better physical stability and better solubility simultaneously, which makes it as a salt of the compound of formula (I) suitable for further drug development.
In another aspect according to the invention, the present application relates to a pharmaceutical composition comprising the salt according to the invention, which comprises the salt according to the invention and a pharmaceutically acceptable carrier.
In still another aspect according to the invention, the present application relates to a method of treating non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutation, comprising administering the salt according to the invention to a patient.
In a further aspect according to the invention, the present application relates to the use of the salt according to the invention in the preparation of a medicament for the treatment of non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutation.
The present application will be illustrated by the following examples.

Examples

The following experimental conditions were used in the examples:

X-ray powder diffractometer (XRPD)
Instrument	Bruker D8 Advance
Detector	LYNXEYE_XE_T (1D model)
Opening angle	2.94°
Scanning mode	Continuous PSD fast mode
Radiation source	Cu/K-Alphal (λ=1.5418Å)
X-ray source power	40 kV, 40 mA
Step size	0.02°
Time per step	0.06 seconds/step
Scanning range	3° to 40°
Slit in primary beam path	Twin_Secondary Motorized slit 10.0 mm according to sample length;
Slit in primary beam path	SollerMount axial Soller angle 2.5°
Slit in secondary beam path	Detector OpticsMount Soller slit 2.5°;
Slit in secondary beam path	Twin_Secondary Motorized slit 5.2 mm
Rotation speed of sample	15 rpm
XRPD plate	monocrystalline silicon wafer, flat plate
or
Instrument	Bruker D8 Advance
Detector	LYNXEYE_XE_T (1D model)
Opening angle	2.94°
Scanning mode	Continuous PSD fast mode
Radiation source	Cu/K-Alphal (λ=1.5418Å)
X-ray source power	40 kV, 40 mA
Step size	0.02°
Time per step	0.12 seconds/step
Scanning range	3° to 40°
Slit in primary beam path	Twin_Secondary Motorized slit 10.0 mm according to sample length;
Slit in primary beam path	SollerMount axial Soller angle 2.5°
Slit in secondary beam path	Detector OpticsMount Soller slit 2.5°;
Slit in secondary beam path	Twin_Secondary Motorized slit 5.2 mm
Rotation speed of sample	15 rpm
XRPD plate	monocrystalline silicon wafer, flat plate

Differential scanning calorimetry (DSC)
Instrument	TA Discovery 2500 or Q2000
Sample pan	Tzero pan and Tzero sealing cap with pinhole
Temperature range	30 to 250°C or before degradation
Rate of temperature rise	10°C/min or 2°C/min
Flow rate of nitrogen	50 mL/min
Sample amount	about 1 to 2 mg

Thermogravimetic analysis (TGA)
Instrument	Discovery 5500 or Q5000
Sample pan	aluminum pan, open
Flow rate of nitrogen	10 mL/min for balance; 25 mL/min for sample
Initial temperature	Environmental condition (lower than 35°C)
Final temperature	300°C or abort next segment if weight < 80%(w/w) (the weight loss of the compound is not greater than 20%(w/w))
Rate of temperature rise	10°C/min
Sample amount	about 2 to 10 mg

Polarizing microscope (PLM)
Instrument	Nikon LV100POL
Method	crossed polarizer, with the addition of silicone oil

Magnetic resonance imaging (NMR)
Instrument		Bruker Avance-AV 400M
Frequency		400 MHz
Probe		5 mm PABBO BB/19F-1H/D Z-GRD Z108618/0406
Number of scans		8
Temperature		297.6K
Relaxation		1 second

High performance liquid chromatography (HPLC)
Instrument	Shimadzu LC40
Wavelength	210 nm
Column	Waters Xbridge C18 3.5 µm, 4.6^∗150 mm
Detector	DAD
Column temperature	40°C
Flow rate	1.0 mL/min
Mobile phase A	20 mmol/L dipotassium hydrogen phosphate solution (adjusted with phosphoric acid to pH=8.05)
Mobile phase B	acetonitrile
Diluent	acetonitrile/water (v:v=1:1)
Injection volume	5 µL

Gradient	Time (min)	Mobile phase A (%)	Mobile phase B (%)
	0	70	30
	2	70	30
	27	45	55
	40	20	80
	45	20	80
	46	70	30
	56	70	30

Ion chromatography (IC)
Instrument	Metrohm 940 professional IC
Sample center	889 IC
Detector	conductivity detector
Eluent (anion)	3.2 mmol/L Na₂CO₃ + 1.0 mmol/L NaHCO₃
Suppressor solution	0.5%H₂SO₄
Column	Anion A SUPP 5-150 or Cation Column C4-150
Column temperature	30°C
Flow rate	0.7 mL/min (anion)
Injection volume	20 µL

The free base concentration and acid ion concentration in the same sample were determined by IC, and the base:acid stoichiometric ratio in this sample was then calculated as follows: $free base : acid ion = \frac{C_{F}}{M_{F}} : \frac{C_{C}}{M_{C}}$
wherein C_F is the free base concentration (mg/mL), M_F is the molar mass of the free base (g/mol), C_C is the acid ion concentration (mg/mL), and M_C is the molar mass of the acid ion (g/mol).

Example 1: amorphous free base (Sample No. Y11526-45-RV FWD1509-AF-SU12)

About 300 mg of the compound of formula (I) (with a purity of 99.9%) were weighed and placed in a 40 mL glass bottle, and 10 mL of methanol/acetonitrile (v:v=1:1) were added to obtain a clear solution. The clear solution was subjected to rapid volatilization (i.e., rotary evaporation) to remove the solvent to afford about 290 mg of an off-white solid in about 97% yield.
HPLC showed that the product had a purity of 99.9%. PLM showed that the product was an irregular sample (Figure 5). XRPD showed that the product was amorphous (Figure 1). DSC showed that the product had a glass-transition temperature of 68.4°C and 104.7°C (Figure 2). TGA showed that the product had a weight loss of about 5.1% at 150°C (Figure 3).
The amorphous free base (Sample No. Y11526-45-RV FWD1509-AF-SU12) was chemically and physically stable at the end of the preparation.

Example 2: amorphous 1 eq. hydrochloride salt (Sample No. Y11526-42-SU11-methanol-dichlorom ethane)

About 300 mg of the compound of formula (I) (with a purity of 99.9%) were weighed and placed in a 40 mL glass bottle, 20 mL of methanol/dichloromethane (v:v=1:1) and 1 eq. of a diluted hydrochloric acid solution (518 µL, 44 mg/mL, in methanol/dichloromethane (v:v=1:1)) were added, and the reaction was performed at 50°C for 2 h to obtain a clear solution. The clear solution was subjected to rapid volatilization to remove the solvent to afford about 306 mg of a pale yellow solid in about 95% yield.
HPLC showed that the product had a purity of 99.9%. PLM showed that the product was an irregular sample (Figure 10). XRPD showed that the product was amorphous (Figure 6). DSC showed that the product had a glass-transition temperature of 128.5°C (Figure 7). TGA showed that the product had a weight loss of about 5.1% at 150°C (Figure 8). IC showed that the product had a free base concentration of 0.5 mg/mL and a chloride ion concentration of 33.7 mg/L, so the base:acid stoichiometric ratio in the product was about 1:1.
The amorphous 1 eq. hydrochloride salt (Sample No. Y11526-42-SU11-methanol-dichloromethane) was chemically and physically stable and reasonable in terms of the base:acid stoichiometric ratio at the end of the preparation.

Example 3: amorphous 2 eq. hydrochloride salt (Sample No. Y11526-28-SU5-methanol-dichloromethane)

About 300 mg of the compound of formula (I) (with a purity of 99.9%) were weighed and placed in a 40 mL glass bottle, 5 mL of methanol/dichloromethane (v:v=1:1) and 2 eq. of a diluted hydrochloric acid solution (1010 µL, 44 mg/mL, in methanol/dichloromethane (v:v=1:1)) were added, and the reaction was performed at 50°C for 2 h, then cooled down to 25°C and continued at this temperature for about 2 h to obtain a clear solution. The resulting clear solution was subjected to rapid volatilization to remove the solvent to afford about 310 mg of a yellow solid in about 90% yield.
HPLC showed that the product had a purity of 99.9%. PLM showed that the product was an irregular sample (Figure 15). XRPD showed that the product was amorphous (Figure 11). DSC showed that the product had a glass-transition temperature of 154.0°C (Figure 12). TGA showed that the product had a weight loss of about 4.3% at 110°C (Figure 13). IC showed that the product had a free base concentration of 0.5 mg/mL and a chloride ion concentration of 77.4 mg/L, so the base:acid stoichiometric ratio in the product was about 1:2.
The amorphous 2 eq. hydrochloride salt (Sample No. Y11526-28-SU5-methanol-dichloromethane) was chemically and physically stable and reasonable in terms of the base:acid stoichiometric ratio at the end of the preparation.

Example 4: amorphous 1 eq. mesylate salt (Sample No. Y11526-42-SU10-methanol-dichloromethane)

The weighed compound of formula (I) was added to acetone (11.70 times by weight with respect to that of the compound of formula (I) weighed) under stirring, and the temperature was increased to 45-55°C. After dissolving, the reaction mixture was filtered while hot, the filtrate was heated to 45-55°C, water (1 time by weight with respect to that of the compound of formula (I) weighed) was added, stirring was continued at 45-55°C, methanesulfonic acid (0.188 times by weight with respect to that of the compound of formula (I) weighed) was added dropwise within 30 min, and the mixture was stirred at 45-55°C for 60±10 min. The reaction mixture was cooled down to 20-30°C within 1.0-2.0 h, and crystallization was performed at 10-30°C under stirring for 1.0-2.0 h. The reaction mixture was filtered, and the filter cake was rinsed twice with acetone (2 * 0.78 times by weight with respect to that of the compound of formula (I) weighed). The filter cake was dried to constant weight under the conditions of 40±5°C and ≤ -0.07 MPa to obtain a high-crystallinity material.
About 300 mg of the high-crystallinity material obtained were weighed, and about 50 mL of methanol/dichloromethane (v:v=1:1) were added to obtain a clear solution. The clear solution was subjected to rapid volatilization to remove the solvent to afford about 268 mg of a pale yellow solid in about 72% yield.
HPLC showed that the product had a purity of 99.9%. PLM showed that the product was an irregular sample (Figure 20). XRPD showed that the product was amorphous (Figure 16). DSC showed that the product had a glass-transition temperature of 111.1°C (Figure 17). TGA showed that the product had a weight loss of about 3.9% at 140°C (Figure 18). ¹H-NMR showed a base:acid stoichiometric ratio of about 1:1 in the product (Figure 19).
The amorphous 1 eq. mesylate salt (Sample No. Y11526-42-SU10-methanol-dichloromethane) was chemically and physically stable and reasonable in terms of the base: acid stoichiometric ratio at the end of the preparation.

Example 5: amorphous 2 eq. mesylate salt (Sample No. Y11526-28-SU4-methanol-dichloromethane)

About 300 mg of the compound of formula (I) (with a purity of 99.9%) were weighed and placed in a 40 mL glass bottle, 2 mL of methanol and 2 eq. of a diluted methanesulfonic acid solution (798 µL, 148 mg/mL, in methanol) were added, and the clear solution became a yellow opaque system. 2 mL of dichloromethane were added, the solution became clear, and 1 mL of methanol/dichloromethane (v:v=1:1) was continued to be added. The reaction was performed at 50° C for 2 h, then cooled down to 25°C and continued at this temperature for about 3 h to obtain a clear solution. The resulting clear solution was subjected to rapid volatilization to remove the solvent to afford about 380 mg of a yellow solid in about 85% yield.
HPLC showed that the product had a purity of 99.9%. PLM showed that the product was an irregular sample (Figure 25). XRPD showed that the product was amorphous (Figure 21). DSC showed that the product had a glass-transition temperature of 131.7°C (Figure 22). TGA showed that the product had a weight loss of about 2.4% at 130°C (Figure 23). ¹H-NMR showed a base:acid stoichiometric ratio of about 1:2 in the product (Figure 24).
The amorphous 2 eq. mesylate salt (Sample No. Y11526-28-SU4-methanol-dichloromethane) was chemically and physically stable and reasonable in terms of the base: acid stoichiometric ratio at the end of the preparation.

Example 6: amorphous 1 eq. besylate salt (Sample No. Y11526-42-SU9-methanol-dichloromethane)

About 300 mg of the compound of formula (I) (with a purity of 99.9%) were weighed and placed in a 250 mL round-bottom flask together with 1 eq. of benzenesulfonic acid, 15 mL of water were added, and the reaction was performed at 50°C for 2 h to obtain a clear solution followed by solid precipitation. The suspension was pre-frozen in a dry ice/ethanol mixture for 2 h, and then water was removed by freeze drying to afford a low-crystallinity sample. The freeze-dried sample was dissolved in 5 mL of methanol/dichloromethane (v:v=1:1) to obtain a clear solution. The clear solution was subjected to rapid volatilization to remove the solvent to afford about 320 mg of a pale yellow solid in about 83% yield.
HPLC showed that the product had a purity of 99.7%. PLM showed that the product was an irregular sample (Figure 30). XRPD showed that the product was amorphous (Figure 26). DSC showed that the product had a glass-transition temperature of 100.7°C and 114.7°C (Figure 27). TGA showed that the product had a weight loss of about 3.8% at 150°C (Figure 28). ¹H-NMR showed a base:acid stoichiometric ratio of about 1:1 in the product (Figure 29).
The amorphous 1 eq. besylate salt (Sample No. Y11526-42-SU9-methanol-dichloromethane) was chemically and physically stable and reasonable in terms of the base:acid stoichiometric ratio at the end of the preparation.

Example 7: amorphous 2 eq. besylate salt (Sample No. Y11526-30-SU1-water)

About 300 mg of the compound of formula (I) (with a purity of 99.9%) were weighed and placed in a 250 mL round-bottom flask together with 2 eq. of benzenesulfonic acid, 15 mL of water were added, and the reaction was performed at 50°C for 2 h to obtain a clear solution. The resulting clear solution was pre-frozen in a dry ice/ethanol mixture for 2 h, and then water was removed by freeze drying to afford about 380 mg of a yellow solid in about 81% yield.
HPLC showed that the product had a purity of 99.7%. PLM showed that the product was an irregular sample (Figure 35). XRPD showed that the product was amorphous (Figure 31). DSC showed that the product had no glass-transition temperature (Figure 32). TGA showed that the product had a weight loss of about 1.9% at 100°C (Figure 33). ¹H-NMR showed a base:acid stoichiometric ratio of about 1:2 in the product (Figure 34).
The amorphous 2 eq. besylate salt (Sample No. Y11526-30-SU1-water) was chemically and physically stable and reasonable in terms of the base:acid stoichiometric ratio at the end of the preparation.

Example 8: amorphous 1 eq. esylate salt (Sample No. Y11526-28-SU7-methanol-dichloromethane)

About 300 mg of the compound of formula (I) (with a purity of 99.9%) were weighed and placed in a 40 mL glass bottle, 5 mL of methanol/dichloromethane (v:v=1:1) and 1 eq. of a diluted ethanesulfonic acid solution (541 µL, 128 mg/mL, in methanol/dichloromethane (v:v=1:1)) were added, and the reaction was performed at 50°C for 2 h, then cooled down to 25°C and continued at this temperature for about 2 h to obtain a clear solution. The resulting clear solution was subjected to rapid volatilization to remove the solvent to afford about 340 mg of a yellow solid in about 90% yield.
HPLC showed that the product had a purity of 99.9%. PLM showed that the product was an irregular sample (Figure 40). XRPD showed that the product was amorphous (Figure 36). DSC showed that the product had a glass-transition temperature of 102.4°C (Figure 37). TGA showed that the product had a weight loss of about 1.6% at 101°C (Figure 38). ¹H-NMR showed a base:acid stoichiometric ratio of about 1:1 in the product (Figure 39).
The amorphous 1 eq. esylate salt (Sample No. Y11526-28-SU7-methanol-dichloromethane) was chemically and physically stable and reasonable in terms of the base: acid stoichiometric ratio at the end of the preparation.

Example 9: amorphous 1 eq. maleate salt (Sample No. Y11526-30-SU2-water)

About 300 mg of the compound of formula (I) (with a purity of 99.9%) were weighed and placed in a 250 mL round-bottom flask together with 1 eq. of maleic acid, 20 mL of water were added, and the reaction was performed at 50°C for 2 h to obtain a clear solution. The resulting clear solution was pre-frozen in a dry ice/ethanol mixture for 2 h, and then water was removed by freeze drying to afford about 330 mg of a pale yellow solid in about 89% yield.
HPLC showed that the product had a purity of 99.9%. PLM showed that the product was an irregular sample (Figure 45). XRPD showed that the product was amorphous (Figure 41). DSC showed that the product had a glass-transition temperature of 89.2°C and 125.2°C (Figure 42). TGA showed that the product had a weight loss of about 0.9% at 100°C (Figure 43). ¹H-NMR showed a base:acid stoichiometric ratio of about 1:1 in the product (Figure 44).
The amorphous 1 eq. maleate salt (Sample No. Y11526-30-SU2-water) was chemically and physically stable and reasonable in terms of the base:acid stoichiometric ratio at the end of the preparation.

Example 10: the crystalline 1 eq. hydrobromide salt (Sample No. Y11526-33-SUS-methanol-dichloromethane)

About 300 mg of the compound of formula (I) (with a purity of 99.9%) were weighed and placed in a 40 mL glass bottle, 20 mL of methanol/dichloromethane (v:v=1:1) and 1 eq. of a diluted hydrobromic acid solution (728 µL, 70 mg/mL, in methanol/dichloromethane (v:v=1:1)) were added, and the reaction was performed at 50°C for 2 h to obtain a nearly clear solution (trace insoluble impurities). The impurities were filtered through a 0.45 µm filter membrane to obtain a clear solution, and the resulting clear solution was subjected to rapid volatilization to remove the solvent to afford about 310 mg of a pale yellow solid in about 90% yield.
HPLC showed that the product had a purity of 99.9%. PLM showed that the product as rod-like and block-like samples (Figure 50). XRPD showed that the product had a high crystallinity (Figure 46). DSC showed that the product started to dehydrate from about 30°C (Figure 47). TGA showed that the product had a weight loss of about 1.8% at 110°C (Figure 48). KF showed that the product contained 1.9% of water. IC showed that the product had a free base concentration of 0.5 mg/mL and a bromide ion concentration of 68.1mg/L, so the base:acid stoichiometric ratio in the product was about 1:1.
The crystalline 1 eq. hydrobromide salt (Sample No. Y11526-33-SU8-methanol-dichloromethane) was chemically and physically stable and reasonable in terms of the base:acid stoichiometric ratio at the end of the preparation.

Example 11: amorphous nitrate salt (Sample No. Y11526-18-RV7-methanol-dichloromethane)

About 100 mg of the compound of formula (I) (with a purity of 99.9%) were weighed and placed in a 40 mL glass bottle, 10 mL of 1,4-dioxane were added, 2 eq. of a diluted nitric acid solution (144 µL, 180 mg/mL, in 1,4-dioxane) were added, and the reaction was performed at 50°C for 2 h. The resulting clear solution was pre-frozen in a dry ice/ethanol mixture for 2 h, and then 1,4-dioxane was removed by freeze drying to afford a nearly amorphous material.
About 80 mg of the nearly amorphous material were weighed and placed in a 40 mL glass bottle, and 10 mL of methanol/dichloromethane (v:v=1:1) were added to obtain a clear solution. The clear solution was subjected to rapid volatilization to remove the solvent to afford the amorphous nitrate salt.
XRPD showed that the product was amorphous (Figure 51). ¹H-NMR showed that the product was degraded (Figure 52).
The amorphous nitrate salt (Sample No. Y11526-18-RV7-methanol-dichloromethane) was at least chemically unstable at the end of the preparation.

Example 12: amorphous sulfate salt (Sample No. Y11526-15-RV3-methanol-acetonitrile)

About 100 mg of the compound of formula (I) (with a purity of 99.9%) were weighed and placed in a 40 mL glass bottle, 10 mL of 1,4-dioxane were added, 2 eq. of a diluted sulfuric acid solution (228 µL, 180.3 mg/mL, in 1,4-dioxane) were added, and the reaction was performed at 50°C for 2 h. The resulting clear solution was pre-frozen in a dry ice/ethanol mixture for 2 h, and then 1,4-dioxane was removed by freeze drying to afford a nearly amorphous material.
About 80 mg of the nearly amorphous material obtained were weighed and placed in a 40 mL glass bottle, and about 10 mL of methanol/acetonitrile (v:v=1:1) were added to obtain a clear solution. The clear solution was subjected to rapid volatilization to remove the solvent to afford the amorphous sulfate salt.
HPLC showed that the product had a purity of 99.7%. PLM showed that the product was an irregular sample (Figure 57). XRPD showed that the product was amorphous (Figure 53). DSC showed that the product had a glass-transition temperature of 103.3°C and 152.8°C (Figure 54). TGA showed that the product had a weight loss of about 3.2% at 100°C (Figure 55). IC showed that the product had a free base concentration of 0.5 mg/mL and a sulfate concentration of 162.5 mg/L, so the base:acid stoichiometric ratio in the product was about 1:1.7, which was unreasonable.
The amorphous sulfate salt (Sample No. Y11526-15-RV3-methanol-acetonitrile) was chemically stable at the end of the preparation, but was physically unstable due to a certain hygroscopicity and unreasonable in terms of the alkali: acid stoichiometric ratio.

Example 13: amorphous 2 eq. p-tosylate salt (Sample No. Y11526-23-FD11-water)

About 100 mg of the compound of formula (I) (with a purity of 99.9%) were weighed and placed in a 40 mL glass bottle together with 2 eq. of p-toluenesulfonic acid, 10 mL of 1,4-dioxane were added, and the reaction was performed at 50°C for 2 h. The resulting clear solution was pre-frozen in a dry ice/ethanol mixture for 2 h, and then 1,4-dioxane was removed by freeze drying to afford a nearly amorphous material. The resulting nearly amorphous material was fully dissolved in 10 mL of water, and the resulting clear solution was pre-frozen in a dry ice/ethanol mixture for 2 h and then water was removed by freeze drying to afford the amorphous 2 eq. p-tosylate salt.
HPLC showed that the product had a purity of 99.6%. PLM showed that the product as a block-like sample (Figure 62). XRPD showed that the product was amorphous (Figure 58). DSC showed that the product had a glass-transition temperature of 98.4°C (Figure 59). TGA showed that the product had a weight loss of about 3.8% at 140°C (Figure 60). ¹H-NMR showed a base:acid stoichiometric ratio of about 1:2 in the product (Figure 61).
The amorphous 2 eq. p-tosylate salt (Sample No. Y11526-23-FD11-water) was chemically stable and reasonable in terms of the base:acid stoichiometric ratio at the end of the preparation, but was physically unstable due to caking and fusion to a glassy state upon short exposure to environmental conditions (Figure 63).

Example 14: amorphous sulfosalicylate salt (Sample No. Y11526-25-FD13-1,4-dioxane)

About 100 mg of the compound of formula (I) (with a purity of 99.9%) were weighed and placed in a 40 mL glass bottle together with 1 eq. of sulfosalicylic acid, 10 mL of 1,4-dioxane were added, and the reaction was performed at 50°C for 2 h. The resulting clear solution was pre-frozen in a dry ice/ethanol mixture for 2 h, and then 1,4-dioxane was removed by freeze drying to afford the amorphous sulfosalicylate salt.
HPLC showed that the product had a purity of 99.7%. PLM showed that the product was an irregular sample (Figure 68). XRPD showed that the product was amorphous (Figure 64). DSC showed that the product had a glass-transition temperature of 72.1°C (Figure 65). TGA showed that the product had a weight loss of about 1.2% at 80°C (Figure 66). ¹H-NMR showed a base:acid stoichiometric ratio of about 1:0.8 in the product (Figure 67), which was unreasonable.
The amorphous sulfosalicylate salt (Sample No. Y11526-25-FD13-1,4-dioxane) was chemically and physically stable, but unreasonable in terms of the base: acid stoichiometric ratio at the end of the preparation.

Example 15: amorphous sulfosalicylate salt (Sample No. Y11526-25-FD12-1,4-dioxane)

About 100 mg of the compound of formula (I) (with a purity of 99.9%) were weighed and placed in a 40 mL glass bottle together with 2 eq. of sulfosalicylic acid, 10 mL of 1,4-dioxane were added, and the reaction was performed at 50°C for 2 h. The resulting clear solution was pre-frozen in a dry ice/ethanol mixture for 2 h, and then 1,4-dioxane was removed by freeze drying to afford the amorphous sulfosalicylate salt.
HPLC showed that the product had a purity of 99.8%. PLM showed that the product was an irregular sample (Figure 73). XRPD showed that the product was amorphous (Figure 69). DSC showed that the product had a glass-transition temperature of 86.3°C (Figure 70). TGA showed that the product had a weight loss of about 2.7% at 110°C (Figure 71). ¹H-NMR showed a base:acid stoichiometric ratio of about 1:1.5 in the product (Figure 72), which was unreasonable.
The amorphous sulfosalicylate salt (Sample No. Y11526-25-FD12-1,4-dioxane) was chemically and physically stable, but unreasonable in terms of the base: acid stoichiometric ratio at the end of the preparation.

Example 16: amorphous L-malate salt (Sample No. Y11526-17-RV6-methanol-dichloromethane)

About 100 mg of the compound of formula (I) (with a purity of 99.9%) were weighed and placed in a 40 mL glass bottle together with 1 eq. of L-malic acid, 10 mL of 1,4-dioxane were added, and the reaction was performed at 50°C for 2 h. The resulting clear solution was pre-frozen in a dry ice/ethanol mixture for 2 h, and then 1,4-dioxane was removed by freeze drying to afford a high-crystallinity material.
About 80 mg of the high-crystallinity material obtained were weighed and placed in a 40 mL glass bottle, and about 10 mL of methanol/dichloromethane (v:v=1:1) were added to obtain a clear solution. The clear solution was subjected to rapid volatilization to remove the solvent to afford the amorphous L-malate salt.
HPLC showed that the product had a purity of 91.1%, that is, the purity of the salt obtained at the end of the preparation was significantly reduced compared with the purity of the free base used to prepare the salt. PLM showed that the product was an irregular sample (Figure 78). XRPD showed that the product was amorphous (Figure 74). DSC showed that the product had a glass-transition temperature of 80.8°C (Figure 75). TGA showed that the product had a weight loss of about 3.3% at 120°C (Figure 76). ¹H-NMR showed a base:acid stoichiometric ratio of about 1:0.6 in the product (Figure 77), which was unreasonable.
The amorphous L-malate salt (Sample No. Y11526-17-RV6-methanol-dichloromethane) was at least chemically unstable and unreasonable in terms of the base: acid stoichiometric ratio at the end of the preparation.

Example 17: amorphous 1 eq. citrate salt (Sample No. Y11526-10-FD6-1,4-dioxane)

About 100 mg of the compound of formula (I) (with a purity of 99.9%) were weighed and placed in a 40 mL glass bottle together with 1 eq. of citric acid, 10 mL of 1,4-dioxane were added, and the reaction was performed at 50°C for 2 h. The resulting clear solution was pre-frozen in a dry ice/ethanol mixture for 2 h, and then 1,4-dioxane was removed by freeze drying to afford the amorphous 1 eq. citrate salt.
HPLC showed that the product had a purity of 94.4%, that is, the purity of the salt obtained at the end of the preparation was significantly reduced compared with the purity of the free base used to prepare the salt. PLM showed that the product was an irregular sample (Figure 83). XRPD showed that the product was amorphous (Figure 79). DSC showed that the product had no glass-transition temperature (Figure 80). TGA showed that the product had a weight loss of about 9.6% at 120°C (Figure 81). ¹H-NMR showed a base:acid stoichiometric ratio of about 1: 1 in the product (Figure 82).
The amorphous 1 eq. citrate salt (Sample No. Y11526-10-FD6-1,4-dioxane) was reasonable in terms of the base:acid stoichiometric ratio, but at least chemically unstable at the end of the preparation.

Example 18: amorphous 1 eq. L-tartrate salt (Sample No. Y11526-10-FD7-1,4-dioxane)

About 100 mg of the compound of formula (I) (with a purity of 99.9%) were weighed and placed in a 40 mL glass bottle together with 1 eq. of L-tartaric acid, 10 mL of 1,4-dioxane were added, and the reaction was performed at 50°C for 2 h. The resulting clear solution was pre-frozen in a dry ice/ethanol mixture for 2 h, and then 1,4-dioxane was removed by freeze drying to afford the amorphous 1 eq. L-tartrate.
HPLC showed that the product was degraded (Figure 88). XRPD showed that the product was amorphous (Figure 84). DSC showed that the product had no glass-transition temperature (Figure 85). TGA showed that the product had a weight loss of about 8.7% at 120°C (Figure 86). ¹H-NMR showed a base:acid stoichiometric ratio of about 1:1 in the product (Figure 87).
The amorphous 1 eq. L-tartrate salt (Sample No. Y11526-10-FD7-1,4-dioxane) was reasonable in terms of the base:acid stoichiometric ratio, but at least chemically unstable at the end of the preparation.
It can be seen from Examples 1-18 that:

when the base:acid molar charge ratio was 1:1, sulfosalicylic acid and L-malic acid cannot enable the resulting salts to have a stoichiometric ratio of compound of formula (I):acid of 1:1;
when the base:acid molar charge ratio was 1:1, hydrochloric acid, methanesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, maleic acid, hydrobromic acid, citric acid, and L-tartaric acid enable the resulting salts to have a stoichiometric ratio of compound of formula (I):acid of 1:1;
when the base:acid molar charge ratio was 1:2, nitric acid, sulfuric acid, and sulfosalicylic acid cannot enable the resulting salts to have a stoichiometric ratio of compound of formula (I):acid of 1:2; and
when the base:acid molar charge ratio was 1:2, hydrochloric acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid enable the resulting salts to have a stoichiometric ratio of compound of formula (I):acid of 1:2.

It can also be seen from Examples 1-18 that:

amorphous 1 eq. citrate salt, amorphous 1 eq. L-tartrate, amorphous nitrate salt and amorphous L-malate salt were chemically unstable at the end of the preparation;
amorphous 2 eq. p-tosylate salt and amorphous sulfate salt were physically unstable at the end of the preparation; and
amorphous 1 eq. hydrochloride salt, amorphous 2 eq. hydrochloride salt, amorphous 1 eq. mesylate salt, amorphous 2 eq. mesylate salt, amorphous 1 eq. besylate salt, amorphous 2 eq. besylate salt, amorphous 1 eq. esylate salt, amorphous 1 eq. maleate salt, crystalline 1 eq. hydrobromide salt, and amorphous sulfosalicylate salt were chemically and physically stable at the end of the preparation.

Example 19: solid storage stability test

Each amorphous salt solid was weighed (two 2 mg samples were weighed for purity testing after solid storage stability study, and one 10 mg sample was weighed for XRPD testing after solid storage stability study) and placed in a glass vial. In a 25°C/60%RH solid storage stability test, the amorphous salt solid was placed in a 25°C/60%RH constant temperature and humidity chamber, and placed in the dark for 1 week (i.e. "solid/25°C/60% RH/open/1 week"), and in a 60°C solid storage stability test, the amorphous salt solid was sealed in an oven at 60°C and heated for 1 week in the dark (i.e. "solid/60°C/closed container/1 week"). Then the sample was taken out for purity testing, crystal form detection and appearance observation, respectively.

Examples 1-10 were subjected to the above solid storage stability tests, and the results are shown in Table 1.

Table 1: Results of the solid storage stability test

Examples	1	2	3	4	5	6	7	8	9	10
Sample	amorphous free base	amorphous 1 eq. hydrochloride salt	amorphous 2 eq. hydrochloride salt	amorphous 1 eq. mesylate salt	amorphous 2 eq. mesylate salt	amorphous 1 eq. besylate salt	amorphous 2 eq. besylate salt	amorphous 1 eq. esylate salt	amorphous 1 eq. maleate salt	crystalline	1 eq. hydrobromide salt
Original purity	99.9%	99.9%	99.9%	99.9%	99.9%	99.7%	99.6%	99.8%	99.8%	99.9%
Original morphology	amorphous	amorphous	amorphous	amorphous	amorphous	amorphous	amorphous	amorphous	amorphous	crystalline

Test BS1: solid/25°C/60% RH/open/1 week
Purity	99.6%	99.9%	99.6%	99.8%	99.9%	98.2%	99.6%	99.9%	997%	99.9%
Color	no color change	no color change	slight color change	no color change	no color change	no color change	slight color change	no color change	slight color change	no color change
Morphology	amorphous (Figure 89), no agglomeration	amorphous (Figure 90), no agglomeration	amorphous (Figure 91), partial agglomeration (Figure 92)	amorphous (Figure 93), no agglomeration	low crystallinity (Figure 94), agglomeration (Figure 95)	amorphous (Figure 96), no agglomeration	caking and fusion to a glassy state (Figure 97)	caking and fusion to a glassy state (Figure 99)	amorphous (Figure 101), agglomeration (Figure 102)	no crystal form change (Figure 103)

Test BS2: solid/60°C/closed container/1 week
Purity	99.9%	98.2%	99.6%	99.9%	99.8%	99.6%	99.4%	99.8%	98.2%	99.9%
Color	no color change	no color change	no color change	no color change	no color change	no color change	no color change	no color change	no color change	no color change
Morphology	medium crystallinity (Figure 89)	amorphous (Figure 90), no agglomeration	amorphous (Figure 91), no agglomeration	amorphous (Figure 93), no agglomeration	amorphous (Figure 94), partial agglomeration (Figure 95)	amorphous (Figure 96), no agglomeration	amorphous (Figure 98), no agglomeration	amorphous (Figure 100), no agglomeration	low crystallinity (Figure 101)	no crystal form change (Figure 103)

The amorphous free base showed good physical and chemical stability under the storage stability test conditions of "solid/25°C/60%RH/open/1 week", and transformed from amorphous to a moderate crystallinity under the storage stability test conditions of "solid/60°C/closed container/1 week".
The amorphous 1 eq. hydrochloride salt showed good physical and chemical stability under the storage stability test conditions of "solid/25°C/60%RH/open/1 week", and had a decrease in purity (about 2%) under the storage stability test conditions of "solid/60°C/closed container/1 week".
The amorphous 2 eq. hydrochloride salt had slight color change and showed a certain hygroscopicity (partial agglomeration) under the storage stability test conditions of "solid/25°C/60%RH/open/1 week", and showed good physical and chemical stability under the storage stability test conditions of "solid/60°C/closed container/1 week".
The amorphous 1 eq. mesylate salt showed good physical and chemical stability under the storage stability test conditions of both "solid/25°C/60%RH/open/1 week" and "solid/60°C/closed container/1 week".
The amorphous 2 eq. mesylate salt transformed from amorphous to a low crystallinity and showed a certain hygroscopicity (agglomeration) under the storage stability test conditions of "solid/25°C/60%RH/open/1 week", and showed a certain hygroscopicity (partial agglomeration) under the storage stability test conditions of "solid/60°C/closed container/1 week".
The amorphous 1 eq. besylate salt had a decrease in purity (about 2%) under the storage stability test conditions of "solid/25°C/60%RH/open/1 week", and showed good physical and chemical stability under the storage stability test conditions of "solid/60°C/closed container/1 week".
The amorphous 2 eq. besylate salt had slight color change and showed significant hygroscopicity (caking and fusion to a glassy state) under the storage stability test conditions of "solid/25°C/60%RH/open/1 week", and showed good physical and chemical stability under the storage stability test conditions of "solid/60°C/closed container/1 week".
The amorphous 1 eq. esylate salt showed significant hygroscopicity (caking and fusion to a glassy state) under the storage stability test conditions of "solid/25°C/60%RH/open/1 week", and showed good physical and chemical stability under the storage stability test conditions of "solid/60°C/closed container/1 week".
The amorphous 1 eq. maleate salt had slight color change and showed a certain hygroscopicity (agglomeration) under the storage stability test conditions of "solid/25°C/60%RH/open/1 week", and had a decrease in purity (about 2%) and transformed from amorphous to a low crystallinity under the storage stability test conditions of "solid/ 60°C/closed container/1 week".
The crystalline 1 eq. hydrobromide salt showed good physical and chemical stability under the storage stability test conditions of both "solid/25°C/60%RH/open/1 week" and "solid/60°C/closed container/1 week".
It can be seen from Example 19 that:

The amorphous 1 eq. besylate salt, amorphous 1 eq. hydrochloride salt and amorphous 1 eq. maleate salt were chemically unstable under the storage conditions of "solid/25°C/60%RH/open/1 week" and/or "solid/60°C/closed container/1 week";
the amorphous 2 eq. hydrochloride salt, amorphous 2 eq. mesylate salt, amorphous 2 eq. besylate salt, amorphous 1 eq. esylate salt, and amorphous 1 eq. maleate salt were physically unstable under the storage conditions of "solid/25°C/60%RH/open/1 week" and/or "solid/60°C/closed container/1 week"; and
the amorphous 1 eq. mesylate salt and crystalline 1 eq. hydrobromide salt were chemically and physically stable under the storage conditions of "solid/25°C/60%RH/open/1 week" and "solid/60°C/closed container/1 week".

Example 20: solid solubility test

5 samples were weighed for each amorphous salt solid (equivalent to 20 mg of free base), and 10 mL of the following solvents were respectively added: 0.1N HCl solution (pH 1.0), 50 mM phosphate buffer (pH 4.5), FeSSIF-V1 (pH 5.0), FaSSIF-V1 (pH 6.5) and SGF (pH 2.0), and stirred at 37°C for 2 h. The suspension was then centrifuged at 37°C, the supernatant was measured for solubility by HPLC, and the solid fraction was measured for XRPD. The target solubility was at least 2 mg (based on free base)/mL.
Examples 1-10 were subjected to the above 2 h solid solubility test, and the results are shown in Table 2. Similarly, Examples 1 and 4 were subjected to a 24 h solid solubility test, and the results are shown in Table 3.

Table 3: Results of the 24 h solid solubility test

Examples 1 4

Sample amorphous free base amorphous 1 eq. mesylate salt

Solubility measured at 24 h (pH) XRPD measured at 24 h Solubility measured at 24 h (pH) XRPD measured at 24 h

Test ES3: FeSSIF-V1 (pH 5.0)

> 2 mg/mL (5.0) clear solution not performed > 2 mg/mL (5.0) clear solution not performed

Test ES4: FaSSIF-V1 (pH 6.5)

> 2 mg/mL (6.8) clear solution not performed > 2 mg/mL (6.6) clear solution not performed
In the 2 h solid solubility test, the amorphous 2 eq. besylate salt did not achieve a solubility of 2 mg/mL in the 0.1N HCl solution (pH 1.0), the crystalline 1 eq. hydrobromide salt did not achieve a solubility of 2 mg/mL in FaSSIF-V1 (pH 6.5), and the amorphous 1 eq. hydrochloride salt, amorphous 2 eq. hydrochloride salt, amorphous 1 eq. mesylate salt, amorphous 2 eq. mesylate salt, amorphous 1 eq. besylate salt, amorphous 1 eq. esylate salt, and amorphous 1 eq. maleate salt had a solubility greater than 2 mg/mL in all solvents tested. Additionally, the amorphous free base and the amorphous 1 eq. mesylate salt had a solubility greater than 2 mg/mL in FeSSIF-V1 (pH 5.0) and FaSSIF-V1 (pH 6.5) in the 24 h solid solubility test.
It can be seen from Examples 1-20 that the amorphous 1 eq. mesylate salt had a reasonable salt-forming equivalent ratio, better chemical stability, better physical stability and better solubility simultaneously.
Although the invention has been described in detail by the detailed description and examples for clarity, these description and examples should not be construed as limiting the scope of the present invention.

Claims

A salt formed from a compound of formula (I) with an acid:
wherein the acid is selected from hydrochloric acid, methanesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, maleic acid, hydrobromic acid, citric acid, L-tartaric acid, and p-toluenesulfonic acid.
The salt according to claim 1, wherein the acid is selected from hydrochloric acid, methanesulfonic acid, and maleic acid.
The salt according to claim 1 or 2, wherein the equivalent ratio of the compound of formula (I) to the acid is 1: 1 or 1:2.
The salt according to claim 3, wherein the acid is methanesulfonic acid.
The salt according to claim 4, wherein the equivalent ratio of the compound of formula (I) to the acid is 1:1.
A pharmaceutical composition comprising the salt according to any one of claims 1-5 and a pharmaceutically acceptable carrier.
A method of treating non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutation, comprising administering the salt according to any one of claims 1-5 or the pharmaceutical composition according to claim 6 to a patient.
Use of the salt according to any one of claims 1-5 in the preparation of a medicament for the treatment of non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutation.